A significant proportion of patients with primary depressive disorder show cortisol hypersecretion, flattened circadian periodicity and failure to suppress plasma cortisol concentration with the overnight dexamethasone test. Increased ACTH levels have also been found in such patients. Recently, abnormalities in suppression of beta-endorphin by dexamethasone have also been demonstrated. Cushing's disease is the classic disease of hypothalamic-pituitary-adrenal axis activation, and patients show elevated cortisol, ACTH and beta-endorphin levels. The patients also have a psychiatric symptom pattern that is characterized by a depressive syndrome. We propose to study the association of abnormalities in ACTH and beta-endorphin-like immunoreactivity (Beta-LPH/Beta-endorphin) with depressed mood in patients with untreated Cushing's syndrome as an approach to understanding the possible involvement of these substances in the pathophysiology of primary depressive disorder. Our hypothesis is that the differences in degree of depressed mood experienced by patients with Cushing's syndrome may be associated with differences in the degree of elevation of plasma Beta-LPH/Beta-endorphin and/or plasma Beta-LPH/Beta-endorphin/ACTH ratios. We plan to study these relationships by determining the association of depressed mood with: a) the level of circulating plasma Beta-LPH/Beta-endorphin in the basal state; b) the plasma Beta-LPH/Beta-endorphin/ACTH ratio in the basal state; c) the response of the Beta-LPH/Beta-endorphin/ACTH ratio to stimulation by metyrapone block of steroidogenesis; d) the response of the plasma Beta-LPH/Beta-endorphin/ACTH ratio during suppression with dexamethasone.